Synthesis method and intermediate of antitumor compound

Abstract

The invention relates to a synthesis method and an intermediate of an anti-tumor compound. The invention belongs to the technical field of medicines, and particularly relates to a synthesis method and an intermediate of an anti-tumor compound. The synthesis method disclosed by the invention has the advantages that the operability is enhanced, the process is simplified, the synthesized target compound can obtain higher purity without a complicated recrystallization process, the generation of three wastes is reduced, and the synthesis method is more suitable for industrial mass production. The intermediate provided by the invention is used for preparing an anti-tumor compound, by-products in the reaction process are effectively reduced, and the total yield of the reaction is increased by at least one time compared with that of an existing synthesis method.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a method for synthesizing an anti-tumor compound and an intermediate thereof. Background Art

[0002] The growth and migration of tumors are not only related to the overexpression of mitotic kinases (such as Aurora kinases), but also rely on the formation of a large number of new blood vessels. Among them, the VEGF / VEGFR (vascular endothelial growth factor / vascular endothelial growth factor receptor) pathway plays a key role in the formation of new blood vessels in tumors.

[0003] Patent WO2018108079A1 discloses a series of compounds that can inhibit, regulate, and / or control the activities of one or more protein kinases such as Aurora kinases and VEGFR kinases, and play an anti-tumor immune effect and anti-tumor efficacy by inhibiting tumor growth, migration, and reversing the tumor microenvironment. The synthesis method of compound 29 is recorded in this patent. Through further research, it is found that its synthesis process still needs to be optimized to obtain a synthesis method with a simpler process, higher yield, higher purity, lower cost, and suitable for large-scale industrial production.

[0004]

[0005] Compound 29 Summary of the Invention

[0006] The present invention provides the following technical solutions 1-14:

[0007] 1. An intermediate compound of formula 2-2 for preparing an anti-tumor compound of formula 7, having the following structural formula:

[0008]

[0009] 2. An intermediate compound of formula (2-3)M for preparing an anti-tumor compound of formula 7, prepared from the aforementioned intermediate compound of formula 2-2, and having the structural formula:

[0010] P1 is selected from Trt.

[0011] 3. An intermediate compound of formula 2M for preparing an anti-tumor compound of formula 7, prepared from the aforementioned intermediate compound of formula (2-3)M, and having the structural formula:

[0012] P1 is selected from Trt.

[0013] 4. An intermediate compound of formula 4M for preparing an anti-tumor compound of formula 7, prepared from the aforementioned intermediate compound of formula 2M, and having the structural formula:

[0014] P1 is selected from Trt.

[0015] 5. An intermediate compound of formula 5M for preparing an antitumor compound of formula 7, which is prepared from the aforementioned intermediate compound of formula 4M, and its structural formula is:

[0016] P1 is selected from Trt.

[0017] 6. An intermediate compound of formula 6M for preparing an antitumor compound of formula 7, which is prepared from the aforementioned intermediate compound of formula 5M, and its structural formula is:

[0018] P1 is selected from Trt.

[0019] 7. An intermediate compound of formula 6M for preparing an antitumor compound of formula 7, which is prepared from the aforementioned intermediate compound of formula 5M, and its structural formula is:

[0020] P1 is selected from Trt;

[0021] The compound of formula 6M is a complex containing 1 molecule of trifluoroacetic acid and 1 molecule of isopropanol.

[0022] 8. A method for synthesizing an intermediate compound of formula 2M:

[0023] (ii) In an organic solvent, the compound of formula 2-2 reacts with an amino protecting reagent to undergo an amino protection reaction to obtain a compound of formula (2-3)M;

[0024] (iii) In an organic solvent, the phthaloyl group of the compound of formula (2-3)M is removed to obtain a compound of formula 2M;

[0025] The reaction formula is as follows:

[0026]

[0027] Among them, the amino protecting reagent is TrtCl.

[0028] 9. According to the method of any one of the foregoing technical solutions, the method for synthesizing an intermediate compound of formula 2M further includes:

[0029] (i) In a solvent, the compound of formula 2-1 reacts with nitric acid to undergo a nitration reaction to obtain a compound of formula 2-2;

[0030] The reaction formula is as follows:

[0031]

[0032] 10. A method for synthesizing an intermediate compound of formula 2M according to any one of the foregoing technical solutions:

[0033] (i) In one or more of concentrated sulfuric acid, acetic anhydride, and acetic acid, the compound of formula 2-1 is subjected to a nitration reaction with nitric acid. The reaction time is 0.5 - 2 hours, and the reaction temperature is 10 - 20 °C to obtain the compound of formula 2-2;

[0034] (ii) In one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and acetonitrile, the compound of formula 2-2 is subjected to an amino protection reaction with an amino protection reagent. The reaction time is 1 - 48 hours, and the reaction temperature is 60 - 100 °C to obtain the compound of formula (2-3)M;

[0035] (iii) In one or more of ethanol, tetrahydrofuran, and acetonitrile, the phthaloyl group of the compound of formula (2-3)M is removed. The reaction time is 1 - 3 hours, and the reaction temperature is the reflux temperature to obtain the compound of formula 2M;

[0036] The reaction formula is as follows:

[0037]

[0038] Among them, the amino protection reagent is TrtCl.

[0039] 11. A method for synthesizing an antitumor compound of formula 7, comprising the following steps:

[0040]

[0041] (a1) Using the method according to any one of the foregoing technical solutions to obtain the compound of formula 2M;

[0042] (a) In an organic solvent, the compound of formula 1 and the compound of formula 2M undergo an aromatic nucleophilic substitution reaction under the action of a base to obtain the compound of formula IM. Whether the compound of formula IM is separated or not, it continues to undergo an aromatic nucleophilic substitution reaction with the compound of formula 3 to obtain the compound of formula 4M;

[0043] (b) In an organic solvent, the compound of formula 4M undergoes a reduction reaction under the action of a catalyst to obtain the compound of formula 5M;

[0044] (c) In an organic solvent, the compound of formula 5M undergoes ring closure under the action of an acid to obtain the compound of formula 6M;

[0045] (d) In an organic solvent, the amino protecting group of the compound of formula 6M is removed to obtain the antitumor compound of formula 7;

[0046] The reaction formula is as follows:

[0047]

[0048] Among them, X1 and X2 are each independently selected from chlorine; P1 is an amino protecting group, and P1 is selected from Trt.

[0049] 12. According to the method of any one of the foregoing technical solutions, in step (a), the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran, and toluene; the base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide;

[0050] Optionally, in step (a),

[0051] The reaction pressure is 0 to 10 MPa (gauge pressure), for example, atmospheric pressure;

[0052] The reaction time is 1 to 96 hours, for example, 17 hours; the reaction temperature can be the reflux temperature;

[0053] Particularly, in the aromatic nucleophilic substitution reaction of the compound of formula 1 and the compound of formula 2M under the action of a base, the reaction time is 3 to 18 hours, for example, the reaction time is 3 to 8 hours; the reaction temperature is 40 °C to 70 °C, for example, the reaction temperature is 40 °C to 60 °C;

[0054] Particularly, in the continued aromatic nucleophilic substitution reaction with the compound of formula 3, the reaction time is 8 hours to 16 hours, for example, 13 hours to 16 hours; the reaction temperature can be the reflux temperature;

[0055] The ratio is:

[0056] Solvent: Compound of formula 1: Compound of formula 2M: Compound of formula 3: Base = 0.5 - 60 L: 0.1 - 11 mol: 1 mol: 0.3 - 30 mol: 0.2 - 25 mol; for example, 5.8 L: 1.1 mol: 1 mol: 3 mol: 2.5 mol;

[0057] Particularly, magnesium sulfate is added in the aromatic nucleophilic substitution reaction of the compound of formula 1 and the compound of formula 2M under the action of a base, and acetic acid is added in the continued aromatic nucleophilic substitution reaction with the compound of formula 3,

[0058] The ratio is:

[0059] Solvent: Compound of formula 1: Compound of formula 2M: Compound of formula 3: Base: Magnesium sulfate: Acetic acid = 0.5 - 60 L: 0.1 - 11 mol: 1 mol: 0.3 - 30 mol: 0.2 - 25 mol: 0.2 - 20 mol: 0.1 - 15 mol, for example, 5.8 L: 1.1 mol: 1 mol: 3 mol: 2.5 mol: 1.6 mol: 1.5 mol;

[0060] The basic condition described in step (a) can use morpholine as the base without adding other bases additionally, or can add one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide; and / or

[0061] and / or

[0062] In step (b), the organic solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetic acid, and acetonitrile; the catalyst is selected from iron powder, platinum oxide, Pt / C, Pd(OH)2 / C, Rh / C, or Pd / C;

[0063] Optionally in step (b), when the catalyst is iron powder, the reaction time is 1 - 96 hours, such as 15 - 24 hours; the reaction pressure is 0 to 10 MPa (gauge pressure), such as atmospheric pressure; the reaction temperature is the reflux temperature;

[0064] The ratio is:

[0065] Organic solvent: Compound of formula 4M: Catalyst = 1 - 130 L: 1 mole: 1 to 150 moles, such as 13 L: 1 mole: 10 - 18 moles, such as 13 L: 1 mole: 14 - 18 moles, such as 13 L: 1 mole: 15 moles;

[0066] Particularly, when the catalyst is iron powder: In step (b), ammonium chloride in an amount of 0.05 - 5 molar equivalents, such as 0.5 molar equivalent, is also added; the solvent is a mixed solvent of ethanol and tetrahydrofuran, for example, the volume ratio of ethanol to tetrahydrofuran is (6 to 10):10;

[0067] Particularly, in step (b), when the catalyst is platinum oxide, Pt / C, Pd(OH)2 / C, Rh / C, or Pd / C, the reaction is carried out at 30 °C to 80 °C for 20 hours to 80 hours in a hydrogen atmosphere; for example, the reaction is carried out at 60 °C to 80 °C for 20 hours to 72 hours in a hydrogen atmosphere; the reaction pressure is greater than 0 to 10 MPa (gauge pressure), such as 0.5 - 2 MPa; the ratio is solvent: Compound of formula 4M: Catalyst = 1 - 50 mL: 1 g: 0.03 to 0.2 g, such as 22 mL: 1 g: 0.1 g;

[0068] Optionally in step (b), a small amount of water is also added in step (b), for example, the volume ratio of water to tetrahydrofuran is (0.2 to 2):10;

[0069] and / or

[0070] In step (c), the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, and hydrochloric acid; the organic solvent is selected from at least one of dichloromethane, methanol, ethanol, and isopropanol;

[0071] Optionally, in step (c), the reaction time is 1 to 96 hours, such as 1.5 to 3 hours; the reaction pressure is 0 to 10 MPa (gauge pressure), such as atmospheric pressure; the reaction temperature is the reflux temperature; the ratio is solvent: compound of formula 5M: acid = 0.5 - 70 L: 1 mole: 0.220 mole, such as 6.6 L: 1 mole: 2 moles

[0072] and / or

[0073] Specifically, step (c) is: the compound of formula 5M is refluxed in isopropanol for 1 to 3 hours under the action of trifluoroacetic acid;

[0074] and / or

[0075] In step (d), the organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, and isopropanol;

[0076] In step (d), an acid is further added, and the acid is selected from at least one of formic acid, acetic acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid;

[0077] In step (d), an alcohol or phenol other than the solvent is further added; the alcohol is selected from methanol and / or ethanol, and the phenol is selected from phenol and / or p-methoxyphenol;

[0078] Optionally, in step (d), the reaction time is 1 to 96 hours, such as 17 hours; the reaction pressure is 0 to 10 MPa (gauge pressure), such as atmospheric pressure; the reaction temperature is the reflux temperature; the ratio is solvent: compound of formula 6M: acid: alcohol or phenol = 10 - 800 L: 1 mole: 0.1 to 10 moles: 0.2 to 20 moles, such as 84 L: 1 mole: 1 mole: 2 moles.

[0079] 13. For the method according to any one of the foregoing technical solutions, the reaction conditions for step (ii) are: reacting at 60 °C to 100 °C for 1 to 48 hours under the action of a base.

[0080] 14. For the method according to any one of the foregoing technical solutions, it further includes the step of synthesizing the compound of formula 1:

[0081] In an organic solvent such as THF, the compound of formula 1-1 and the compound of formula 1-2 are subjected to a coupling reaction to obtain the compound of formula 1;

[0082] The reaction formula is as follows:

[0083]

[0084] Wherein, X1, X2 and X3 are each independently selected from chlorine.

[0085] In a first aspect, the present invention provides the following technical solutions 1-15:

[0086] 1. A method for synthesizing a compound of formula 7 having antitumor activity, comprising the following steps:

[0087]

[0088] (a) In an organic solvent, reacting a compound of formula 1 with a compound of formula 2M under the action of a base to undergo an aromatic nucleophilic substitution reaction to obtain a compound of formula IM. Whether the compound of formula IM is separated or not, it is then reacted with a compound of formula 3 to continue the aromatic nucleophilic substitution reaction, for example, reacting with a compound of formula 3 under basic conditions to continue the aromatic nucleophilic substitution reaction, to obtain a compound of formula 4M;

[0089] (b) In an organic solvent, reducing the compound of formula 4M under the action of a catalyst to obtain a compound of formula 5M;

[0090] (c) In an organic solvent, cyclizing the compound of formula 5M under the action of an acid to obtain a compound of formula 6M;

[0091] (d) In an organic solvent, removing the amino protecting group from the compound of formula 6M to obtain a compound of formula 7 having antitumor activity;

[0092] The reaction scheme is as follows:

[0093]

[0094] Wherein, X1 and X2 are each independently selected from halogen; P1 is an amino protecting group, preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, such as Boc, Cbz, Tos, Fmoc, PMB, Trt or THP; P1 is connected to any N atom on the ring where it is located, preferably P1 is connected to the N atom adjacent to the methyl group on the ring where it is located.

[0095] 2. A method for synthesizing a compound of formula 7 having antitumor activity,

[0096]

[0097] characterized by comprising the following steps:

[0098] (d) In an organic solvent, removing the amino protecting group from the compound of formula 6M to obtain a compound of formula 7 having antitumor activity;

[0099] The reaction scheme is as follows:

[0100]

[0101] Among them, P1 is an amino protecting group. Preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, such as Boc, Cbz, Tos, Fmoc, PMB, Trt or THP; P1 is connected to any N atom on the ring where it is located. Preferably, P1 is connected to the N atom adjacent to the methyl group on the ring where it is located.

[0102] 3. A method for synthesizing a compound of formula 6M intermediate or the method according to any one of the foregoing technical solutions,

[0103]

[0104] which is characterized in that it comprises the following steps:

[0105] (c) In an organic solvent, cyclize the compound of formula 5M under the action of an acid to obtain a compound of formula 6M;

[0106] The reaction formula is as follows:

[0107]

[0108] Among them, P1 is an amino protecting group. Preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, such as Boc, Cbz, Tos, Fmoc, PMB, Trt or THP; P1 is connected to any N atom on the ring where it is located. Preferably, P1 is connected to the N atom adjacent to the methyl group on the ring where it is located.

[0109] 4. A method for synthesizing a compound of formula 5M intermediate or the method according to any one of the foregoing technical solutions,

[0110]

[0111] which is characterized in that it comprises the following steps:

[0112] (b) In an organic solvent, carry out a reduction reaction on the compound of formula 4M under the action of a catalyst to obtain a compound of formula 5M;

[0113] The reaction formula is as follows:

[0114]

[0115] Among them, P1 is an amino protecting group. Preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, such as Boc, Cbz, Tos, Fmoc, PMB, Trt or THP; P1 is connected to any N atom on the ring where it is located. Preferably, P1 is connected to the N atom adjacent to the methyl group on the ring where it is located.

[0116] 5. A method for synthesizing an intermediate compound of formula 4M or the method according to any one of the foregoing technical solutions,

[0117]

[0118] which is characterized by comprising the following steps:

[0119] (a) In an organic solvent, the compound of formula 1 and the compound of formula 2M undergo an aromatic nucleophilic substitution reaction under the action of a base to obtain a compound of formula IM. Whether the compound of formula IM is separated or not, it continues to undergo an aromatic nucleophilic substitution reaction with the compound of formula 3, for example, continues to undergo an aromatic nucleophilic substitution reaction with the compound of formula 3 under basic conditions, to obtain a compound of formula 4M;

[0120] The reaction formula is as follows:

[0121]

[0122] Among them, X1 and X2 are each independently selected from halogen; P1 is an amino protecting group. Preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, such as Boc, Cbz, Tos, Fmoc, PMB, Trt or THP; P1 is connected to any N atom on the ring where it is located. Preferably, P1 is connected to the N atom adjacent to the methyl group on the ring where it is located.

[0123] 6. The method according to any one of the foregoing technical solutions, wherein in step (a), the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran and toluene; the base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide;

[0124] Optionally, in step (a),

[0125] the reaction pressure is 0 to 10 MPa (gauge pressure), such as atmospheric pressure;

[0126] the reaction time is 1 to 96 hours, such as 17 hours; the reaction temperature can be the reflux temperature;

[0127] Specifically, in the aromatic nucleophilic substitution reaction between the compound of Formula 1 and the compound of Formula 2M under the action of a base, the reaction time is 3 - 18 hours, for example, the reaction time is 3 - 8 hours; the reaction temperature is 40°C to 70°C, for example, the reaction temperature is 40°C to 60°C;

[0128] Specifically, in the subsequent aromatic nucleophilic substitution reaction with the compound of Formula 3, the reaction time is 8 hours to 16 hours, for example, 13 hours to 16 hours; the reaction temperature can be the reflux temperature;

[0129] The ratio is:

[0130] Solvent: Compound of Formula 1: Compound of Formula 2M: Compound of Formula 3: Base = 0.5 - 60 L: 0.1 - 11 mol: 1 mol: 0.3 - 30 mol: 0.2 - 25 mol; for example, 5.8 L: 1.1 mol: 1 mol: 3 mol: 2.5 mol;

[0131] Specifically, magnesium sulfate is added in the aromatic nucleophilic substitution reaction between the compound of Formula 1 and the compound of Formula 2M under the action of a base, and acetic acid is added in the subsequent aromatic nucleophilic substitution reaction with the compound of Formula 3.

[0132] The ratio is:

[0133] Solvent: Compound of Formula 1: Compound of Formula 2M: Compound of Formula 3: Base: Magnesium sulfate: Acetic acid = 0.5 - 60 L: 0.1 - 11 mol: 1 mol: 0.3 - 30 mol: 0.2 - 25 mol: 0.2 - 20 mol: 0.1 - 15 mol, for example, 5.8 L: 1.1 mol: 1 mol: 3 mol: 2.5 mol: 1.6 mol: 1.5 mol.

[0134] 7. The method according to any one of the foregoing technical solutions, wherein in step (b), the organic solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, 2 - methyltetrahydrofuran, acetic acid, and acetonitrile; the catalyst is selected from iron powder, platinum oxide, Pt / C, Pd(OH)2 / C, Rh / C, or Pd / C;

[0135] Optionally, in step (b), when the catalyst is iron powder, the reaction time is 1 - 96 hours, for example, 15 - 24 hours; the reaction pressure is 0 to 10 MPa (gauge pressure), for example, atmospheric pressure; the reaction temperature is the reflux temperature;

[0136] The ratio is:

[0137] Organic solvent: Compound of Formula 4M: Catalyst = 1 - 130 L: 1 mol: 1 to 150 mol, for example, 13 L: 1 mol: 10 - 18 mol, for example, 13 L: 1 mol: 14 - 18 mol, for example, 13 L: 1 mol: 15 mol;

[0138] In particular, when the catalyst is iron powder: in step (b), 0.05 - 5 moles, such as 0.5 moles, of ammonium chloride is further added; the solvent is a mixed solvent of ethanol and tetrahydrofuran. For example, the volume ratio of ethanol to tetrahydrofuran is (6 to 10):10;

[0139] In particular, in step (b), when the catalyst is platinum oxide, Pt / C, Pd(OH)2 / C, Rh / C or Pd / C, the reaction is carried out at 30°C to 80°C for 20 hours to 80 hours in a hydrogen atmosphere; for example, the reaction is carried out at 60°C to 80°C for 20 hours to 72 hours in a hydrogen atmosphere; the reaction pressure is greater than 0 to 10 MPa (gauge pressure), such as 0.5 - 2 MPa; the ratio is solvent: compound of formula 4M: catalyst = 1 - 50 mL: 1 g: 0.03 to 0.2 g, such as 22 mL: 1 g: 0.1 g;

[0140] Optionally in step (b), a small amount of water is further added in step (b). For example, the volume ratio of water to tetrahydrofuran is (0.2 to 2):10.

[0141] 8. The method according to any one of the foregoing technical solutions, wherein in step (c), the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid and hydrochloric acid; the organic solvent is selected from at least one of dichloromethane, methanol, ethanol and isopropanol;

[0142] Optionally in step (c), the reaction time is 1 - 96 hours, such as 1.5 - 3 hours; the reaction pressure is 0 to 10 MPa (gauge pressure), such as atmospheric pressure; the reaction temperature is the reflux temperature; the ratio is solvent: compound of formula 5M: acid = 0.5 - 70 L: 1 mole: 0.220 mole, such as 6.6 L: 1 mole: 2 moles.

[0143] 9. The method according to any one of the foregoing technical solutions, wherein step (c) is specifically: the compound of formula 5M is in isopropanol and undergoes a reflux reaction for 1 hour to 3 hours under the action of trifluoroacetic acid.

[0144] 10. The method according to any one of the foregoing technical solutions, wherein in step (d), the organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol and isopropanol;

[0145] In step (d), an acid is further added, and the acid is selected from at least one of formic acid, acetic acid, hydrochloric acid, methanesulfonic acid and trifluoroacetic acid;

[0146] In step (d), an alcohol or phenol other than the solvent is further added; the alcohol is selected from methanol and / or ethanol, and the phenol is selected from phenol and / or p-methoxyphenol;

[0147] Optionally, in step (d), the reaction time is 1 to 96 hours, such as 17 hours; the reaction pressure is 0 to 10 MPa (gauge pressure), such as atmospheric pressure; the reaction temperature is the reflux temperature; the ratio is solvent: compound of formula 6M: acid: alcohol or phenol = 10 - 800 L: 1 mole: 0.1 to 10 moles: 0.2 to 20 moles, such as 84 L: 1 mole: 1 mole: 2 moles.

[0148] 11. The method according to any one of the foregoing technical solutions, characterized in that it further comprises a step of synthesizing a compound of formula 2M:

[0149] (i) In a solvent such as concentrated sulfuric acid, acetic anhydride, acetic acid, carry out a nitration reaction on a compound of formula 2-1 (for example, 1 molar equivalent) with nitric acid (for example, 1 - 2 molar equivalents) (reaction time: 0.5 - 2 hours, reaction temperature; 10 - 20 °C) to obtain a compound of formula 2-2;

[0150] (ii) In one or more of organic solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and acetonitrile, carry out an amino protection reaction on the compound of formula 2-2 (for example, 1 molar equivalent) with an amino protection reagent (for example, 1 - 1.5 molar equivalents) (reaction time 1 - 48 hours, reaction temperature 60 - 100 °C) to obtain a compound of formula (2-3)M;

[0151] (iii) In one or more of organic solvents such as ethanol, tetrahydrofuran and acetonitrile, dephthaloylize the compound of formula (2-3)M (for example, 1 molar equivalent) (for example, reaction time: 1 - 3 hours, reaction temperature: reflux temperature) to obtain a compound of formula 2M;

[0152] The reaction formula is as follows:

[0153]

[0154] Wherein, the amino protection reagent is Boc2O, CbzCl, TosCl, FmocCl, PMBBr, MOMCl, EOMCl, tert-butanol, isobutene, BnCl, acetic anhydride, SEMCl, TrtCl or DHP, such as Boc2O, CbzCl, TosCl, FmocCl, PMBBr, TrtCl or DHP; P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, such as Boc, Cbz, Tos, Fmoc, PMB, Trt or THP; P1 is connected to any N atom on the ring where it is located, preferably P1 is connected to the N atom adjacent to the methyl group on the ring where it is located.

[0155] 12. The method according to technical solution 11, characterized in that

[0156] When the amino protecting reagent is TrtCl, the reaction conditions for step (ii) are: under the action of a base, reacting at 60°C to 100°C for 1 hour to 48 hours;

[0157] When the amino protecting reagent is DHP, the reaction conditions for step (ii) are: under the action of p-toluenesulfonic acid or pyridinium p-toluenesulfonate, refluxing at 60°C to 100°C for 3 hours to 48 hours.

[0158] 13. The method according to any one of the foregoing technical solutions, characterized in that it further comprises the step of synthesizing the compound of formula 1:

[0159] In an organic solvent such as THF, the compound of formula 1-1 (for example, 1 to 2 molar equivalents) is coupled with the compound of formula 1-2 (for example, 1 to 2 molar equivalents) (reaction time: 2 - 4 hours, reaction temperature: -70 to 60°C) to obtain the compound of formula 1;

[0160] The reaction formula is as follows:

[0161]

[0162] Wherein, X1, X2 and X3 are each independently selected from halogen; preferably, X1, X2 and X3 are each independently selected from chlorine.

[0163] 14. An intermediate for preparing the antitumor compound of formula 7, characterized in that it has the following structural formula:

[0164]

[0165] Wherein, X1 and X2 are each independently selected from halogen;

[0166] P1 is selected from Trt or THP; P1 is connected to any N atom on the ring where it is located, preferably P1 is connected to the N atom adjacent to the methyl group on the ring where it is located.

[0167] 15. An intermediate for preparing the antitumor compound of formula 7, characterized in that it has the following structural formula:

[0168]

[0169] Wherein, P1 is selected from Trt or THP; P1 is connected to any N atom on the ring where it is located, preferably P1 is connected to the N atom adjacent to the methyl group on the ring where it is located;

[0170] The formula 6M is a complex containing 1 molecule of trifluoroacetic acid and 1 molecule of isopropanol.

[0171] In a second aspect, the object of the present invention is to provide a method for synthesizing the antitumor compound of formula 7, comprising the following steps:

[0172]

[0173] (a) In an organic solvent, the compound of formula 1 and the compound of formula 2 undergo an aromatic nucleophilic substitution reaction under the action of a base, and then continue to undergo an aromatic nucleophilic substitution reaction with the compound of formula 3, for example, continue to undergo an aromatic nucleophilic substitution reaction with the compound of formula 3 under basic conditions, to obtain the compound of formula 4;

[0174] (b) In an organic solvent, the compound of formula 4 undergoes a reduction reaction under the action of a catalyst to obtain the compound of formula 5;

[0175] (c) In an organic solvent, the compound of formula 5 undergoes ring closure under the action of an acid to obtain the compound of formula 6;

[0176] (d) In an organic solvent, the compound of formula 6 is deprotected from the amino group to obtain the anti-tumor compound of formula 7;

[0177] The reaction formula is as follows:

[0178]

[0179] Wherein, X1 and X2 are each independently selected from halogen; P1 is an amino protecting group, and P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example, Boc, Cbz, Tos, Fmoc, PMB, Trt or THP.

[0180] In one embodiment, in step (a), the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran, and toluene; the base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide.

[0181] In one embodiment, in step (b), the organic solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile; the catalyst is selected from iron powder, platinum oxide, Pt / C, or Pd / C.

[0182] In one embodiment, in step (c), the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, and hydrochloric acid; the organic solvent is at least one selected from dichloromethane, methanol, ethanol, and isopropanol.

[0183] In one embodiment, step (c) is specifically: the compound of formula 5 is refluxed in isopropanol for 1 hour to 3 hours, for example, 1.5 hours to 3 hours, under the action of trifluoroacetic acid.

[0184] In one embodiment, in step (d), the organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, and isopropanol;

[0185] In step (d), a catalyst is further added, and the catalyst is selected from at least one of formic acid, acetic acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid;

[0186] In step (d), an alcohol or a phenol is further added; the alcohol is selected from methanol and / or ethanol, and the phenol is selected from phenol and / or p-methoxyphenol.

[0187] In one embodiment, it further includes the step of synthesizing the compound of formula 2:

[0188] (i) In a solvent, the compound of formula 2-1 is subjected to a nitration reaction with nitric acid to obtain the compound of formula 2-2;

[0189] (ii) In an organic solvent, the compound of formula 2-2 is subjected to an amino protection reaction with an amino protecting reagent to obtain the compound of formula 2-3;

[0190] (iii) In an organic solvent, the phthaloyl group of the compound of formula 2-3 is removed to obtain the compound of formula 2;

[0191] The reaction formula is as follows:

[0192]

[0193] Among them, the amino protecting reagent is Boc2O, CbzCl, TosCl, FmocCl, PMBBr, MOMCl, EOMCl, tert-butanol, isobutene, BnCl, acetic anhydride, SEMCl, TrtCl, or DHP, such as Boc2O, CbzCl, TosCl, FmocCl, PMBBr, TrtCl, or DHP; P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt, or THP, such as Boc, Cbz, Tos, Fmoc, PMB, Trt, or THP.

[0194] In one embodiment, when the amino protecting reagent is TrtCl, the reaction conditions for step (ii) are: under the action of a base, reacting at 60 °C to 100 °C for 1 hour to 48 hours;

[0195] When the amino protecting reagent is DHP, the reaction conditions for step (ii) are: under the action of p-toluenesulfonic acid or pyridinium p-toluenesulfonate, refluxing at 60 °C to 100 °C for 3 hours to 48 hours.

[0196] In one embodiment, it further includes the step of synthesizing Compound 1:

[0197] In an organic solvent, Compound 1-1 and Compound 1-2 are subjected to a coupling reaction to obtain Compound 1;

[0198] The reaction formula is as follows:

[0199]

[0200] Wherein, X1, X2 and X3 are each independently selected from halogen; preferably, X1, X2 and X3 are each independently selected from chlorine.

[0201] In a third aspect, the present invention also provides an intermediate for preparing the anti-tumor Compound 7, having the following structural formula:

[0202]

[0203] Wherein, X1 and X2 are each independently selected from halogen;

[0204] P1 is selected from Trt or THP;

[0205] P2 is selected from Trt or THP, and P3 does not exist; or P3 is selected from Trt or THP, and P2 does not exist;

[0206] PG1 is an acetyl group or PG1-NH- is

[0207] represents a possible single bond or double bond.

[0208] In a fourth aspect, the present invention provides an intermediate for preparing the anti-tumor Compound 7, having the following structural formula:

[0209]

[0210] Wherein, P1 is selected from Trt or THP;

[0211] This Formula 6 is a complex containing 1 molecule of trifluoroacetic acid and 1 molecule of isopropanol.

[0212] Compared with the prior art, the present invention has the following beneficial effects:

[0213] (1) Different from the existing synthesis process that first deprotects and then forms the tricyclic ring, the present invention adopts the method of first synthesizing the tricyclic ring and then deprotecting. Using the intermediate (compound of formula 2) as the raw material, after aromatic nucleophilic substitution reaction and reduction reaction, the compound of formula 5 is obtained. Thus, the process of first forming the tricyclic ring and then deprotecting can be realized for the compound of formula 5, thereby avoiding the deficiencies in the existing process: ① the problem of generating waste water due to the need to use a large amount of trifluoroacetic acid during the prior deprotection; ② the problem of poor operability and complex post-treatment when using stannous chloride to reduce and form the ring in the subsequent formation of the tricyclic ring; ③ the overall process is complex and needs to be achieved by column chromatography.

[0214] (2) The synthesis method of the present invention has enhanced operability, simplifies the process. The synthesized compound of formula 7 can obtain higher purity without further complex recrystallization process, reduces the generation of three wastes, and is more suitable for industrial large-scale production.

[0215] (3) The intermediate compound of formula 2-2 provided by the present invention has its amino protected by two acyl groups, with specific high selectivity. It can almost completely attach the Trt protecting group to the target N on the pyrazole ring, obtaining a single selective product, thus bringing a significant high yield of 88.4%. It is used to prepare anti-tumor compounds, effectively reducing by-products in the reaction process, improving the total yield of the reaction, and at least doubling the synthesis method of compound 29 in the previous patent WO2018108079A1. Detailed Embodiments

[0216] The above content of the present invention will be further described in detail through specific embodiments below, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0217] The abbreviations used herein have the meanings commonly understood in the art as follows:

[0218] "Halogen" refers to fluorine, chlorine, bromine, iodine, etc.;

[0219] "Boc2O" refers to: di-tert-butyl dicarbonate;

[0220] "Boc" refers to: tert-butoxycarbonyl;

[0221] "CbzCl" refers to: benzyl chloroformate;

[0222] "Cbz" refers to: benzyloxycarbonyl;

[0223] "TosCl" refers to: p-toluenesulfonyl chloride;

[0224] "Tos" means: tosyl; "FmocCl" means: 9-fluorenylmethyl chloroformate; "Fmoc" means: 9-fluorenylmethyloxycarbonyl; "PMBBr" means: p-methoxybenzyl bromide; "PMB" means: p-methoxybenzyl; "MOMCl" means: chloromethyl methyl ether; "MOM" means: methoxymethyl; "EOMCl" means: chloromethyl ethyl ether; "EOM" means: ethoxymethyl; "tBu" means: tert-butyl; "BnCl" means: benzyl chloride; "Bn" means: benzyl; "Ac" means: acetyl; "SEMCl" means: 2-(trimethylsilyl)ethoxymethyl chloride; "SEM" means: 2-(trimethylsilyl)ethoxymethyl; "TrtCl" means: triphenylmethyl chloride; "Trt" means: triphenylmethyl; "DHP" means: 3,4-dihydro-2H-pyran; "THP" means: 2-tetrahydropyranyl; "THF" means: tetrahydrofuran; "2-MeTHF" means: 2-methyltetrahydrofuran; "MTBE" means: methyl tert-butyl ether; "ACN" means: acetonitrile; "TEA" means: triethylamine; "TFA" means: trifluoroacetic acid;

[0225] "IPA" means: isopropyl alcohol;

[0226] “TEMPO" means: 2,2,6,6-tetramethylpiperidin-1-oxyl;

[0227] “DCM" means: dichloromethane;

[0228] “TLC" means: thin layer chromatography;

[0229] “HNMR" means: proton nuclear magnetic resonance spectroscopy;

[0230] “DMSO" means: dimethyl sulfoxide;

[0231] “HPLC" means: high performance liquid chromatography;

[0232] “PE" means: petroleum ether;

[0233] “EA" means: ethyl acetate;

[0234] “LC-MS" means: liquid chromatography - mass spectrometry.

[0235] In the present invention, the catalyst includes substances that can change the reaction rate in the conventional sense, and also includes substances that play an oxidation-reduction role or an acid-base role in the reaction.

[0236] In the present invention, unless otherwise specified, the reaction is carried out under normal pressure.

[0237] In the present invention, the reaction temperature refers to the highest temperature reached during the reaction process. The entire reaction process or a part of the reaction process is carried out at the highest temperature.

[0238] In the present invention, when referring to "a ratio of", for example, solvent: compound of formula 1: compound of formula 2M: compound of formula 3: base = 5.8L: 1.1 mol: 1 mol: 3 mol: 2.5 mol, this expression refers to the proportional relationship of the feed amount of each material in the reaction process, that is, if 1 mol of compound of formula 2M is fed, the feed amounts of solvent, compound of formula 1, compound of formula 3 and base are 5.8L, 1.1 mol, 3 mol and 2.5 mol respectively. If the feed amount of compound of formula 2M increases or decreases, the feed amounts of other materials increase or decrease proportionally. The feed amount of each material is the sum of the feed amounts of the material in the reaction process. For example, if a certain material is fed once, the feed amount is the amount of the one-time feed. If a certain material is fed multiple times, the feed amount is the sum of the feed amounts of the multiple times. The various materials mentioned in the ratio can be fed simultaneously or separately.

[0239] In the present invention, the chemical structural formula represents the free base or free acid form of the compound represented by the formula, as well as hydrates, solvates, acid salts, basic salts, and combinations thereof. For example, the following formula A may include the free base form of formula A, as well as various complexes of formula A, such as a complex containing 1 molecule of trifluoroacetic acid and 1 molecule of isopropanol (as shown in the following formula B):

[0240]

[0241] The present invention provides a method for synthesizing an antitumor compound of formula 7, comprising the following steps:

[0242]

[0243] (a) in an organic solvent, reacting a compound of Formula 1 with a compound of Formula 2M under the action of a base to obtain a compound of Formula IM, and reacting the compound of Formula IM with a compound of Formula 3 with or without separation to further undergo an aromatic nucleophilic substitution reaction, for example, reacting the compound of Formula 3 with a compound of Formula 3 under alkaline conditions to further undergo an aromatic nucleophilic substitution reaction to obtain a compound of Formula 4M;

[0244] (b) reducing the compound of formula 4M in an organic solvent in the presence of a catalyst to obtain a compound of formula 5M;

[0245] (c) in an organic solvent, subjecting the compound of formula 5M to ring closure under the action of an acid to obtain a compound of formula 6M;

[0246] (d) removing the amino protecting group from the compound of formula 6M in an organic solvent to obtain an antitumor compound of formula 7;

[0247] The reaction formula is as follows:

[0248]

[0249] Wherein, X1 and X2 are each independently selected from halogen; P1 is an amino protecting group, and preferably P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, such as Boc, Cbz, Tos, Fmoc, PMB, Trt or THP; P1 is connected to any N atom on the ring where it is located, and preferably P1 is connected to the N atom adjacent to the methyl group on the ring where it is located.

[0250] In some embodiments, the compound of formula 2M includes the following compound of formula 2 and compound of formula 2m:

[0251] Preferably, the compound of formula 2M is the compound of formula 2.

[0252] The compound of formula IM includes the following compound of formula I and compound of formula Im:

[0253] Preferably, the compound of formula IM is the compound of formula I.

[0254] The compound of formula 4M includes the following compound of formula 4 and compound of formula 4m:

[0255] Preferably, the compound of formula 4M is the compound of formula 4.

[0256] The compound of formula 5M includes the following compound of formula 5 and compound of formula 5m:

[0257] Preferably, the compound of formula 5M is the compound of formula 5.

[0258] The compound of formula 6M includes the following compound of formula 6 and compound of formula 6m:

[0259] Preferably, the compound of formula 6M is the compound of formula 6.

[0260] Preferably, P1 is selected from Trt or THP.

[0261] In some embodiments, the synthesis method of the compound of formula 4 is step (a): in an organic solvent, the compound of formula 1 reacts with the compound of formula 2 under the action of a base to undergo an aromatic nucleophilic substitution reaction to obtain the compound of formula I. Without separation, the compound of formula IM continues to undergo an aromatic nucleophilic substitution reaction with the compound of formula 3, for example, continues to undergo an aromatic nucleophilic substitution reaction with the compound of formula 3 under basic conditions, to obtain the compound of formula 4.

[0262] When synthesizing the compound of formula 4 in the present invention, it is not necessary to separate the product I after reacting the compound of formula 1 with the compound of formula 2, but directly react with the compound of formula 3, which simplifies the process and improves the yield.

[0263] In some embodiments, in step (a), the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran, and toluene.

[0264] Preferably, the organic solvent is selected from 2-methyltetrahydrofuran or acetonitrile.

[0265] In some embodiments, in step (a), the base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide.

[0266] In some embodiments, in step (a), for the basic condition, no additional base may be added, using morpholine as the base, or an additional basic reagent may be added, such as one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide. In some embodiments, in step (a), the base is sodium hydride and the solvent is 2-methyltetrahydrofuran.

[0267] In some embodiments, in step (a), the conditions for the aromatic nucleophilic substitution reaction between the compound of formula 1 and the compound of formula 2 are: reacting at 40 °C to 70 °C for 3 hours to 18 hours; for example, reacting at 40 °C to 60 °C for 3 hours to 8 hours.

[0268] In some embodiments, in step (a), the conditions for the continued aromatic nucleophilic substitution reaction with the compound of formula 3 are: refluxing for 8 hours to 16 hours; for example, refluxing for 8 hours to 12 hours; or for example, refluxing for 13 hours to 16 hours.

[0269] In some embodiments, in step (a), the molar ratio of the compound of formula 1, the compound of formula 2, and the compound of formula 3 is (1 to 1.2):1:3.

[0270] In some embodiments, in step (a), magnesium sulfate, molecular sieve, or activated carbon can also be added as a catalyst.

[0271] Particularly, when adding magnesium sulfate as a catalyst, the addition amount of magnesium sulfate is 0.2 to 3 molar equivalents of the compound of formula 2; for example, the addition amount of magnesium sulfate is 2 to 3 molar equivalents of the compound of formula 2; or for example, the addition amount of magnesium sulfate is 1 to 3 molar equivalents of the compound of formula 2.

[0272] Furthermore, after the reaction in step (a) is completed, the compound of formula 4 is purified, and the purification operation can be carried out by conventional methods in the art.

[0273] The present invention also provides another method for synthesizing Compound 4, which comprises the following steps:

[0274] In an organic solvent, an aromatic nucleophilic substitution reaction occurs between Compound 1 and Compound 2 under the action of a base to obtain Compound I;

[0275] In an organic solvent, an aromatic nucleophilic substitution reaction occurs between Compound I and the above Compound 3 under the action of a base to obtain Compound 4;

[0276] The reaction formula is as follows:

[0277]

[0278] Wherein, X1 and X2 are each independently selected from halogen; P1 is an amino protecting group, preferably P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, such as Boc, Cbz, Tos, Fmoc, PMB, Trt or THP.

[0279] In this method, the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran and toluene. The base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide.

[0280] In some embodiments, the synthesis steps and reaction conditions of Compound 4m are as described in the synthesis method of Compound 4 above, except that Compound 2 is replaced by Compound 2m and Compound I is replaced by Compound Im.

[0281] In some embodiments, the synthesis method of Compound 5 is step (b): In an organic solvent, Compound 4 undergoes a reduction reaction under the action of a catalyst to obtain Compound 5.

[0282] In some embodiments, in step (b), the organic solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetic acid and acetonitrile.

[0283] In some embodiments, in step (b), the catalyst is selected from iron powder, platinum oxide, Pt / C, Pd(OH)2 / C, Rh / C or Pd / C.

[0284] In some embodiments, the mass fraction of Pt / C and Rh / C is 5%; the mass fraction of Pd / C is 5%, 10%; the mass fraction of Pd(OH)2 / C is 10%, 20%.

[0285] When the catalyst is iron powder, the addition amount of the iron powder is 10 to 18 molar equivalents of the compound of formula 4; for example, the addition amount of the iron powder is 14 to 18 molar equivalents of the compound of formula 4.

[0286] Particularly, ammonium chloride is further added in step (b), and the addition amount of the ammonium chloride is 0.4 to 0.6 molar equivalents of the compound of formula 4; the solvent is a mixed solvent of ethanol and tetrahydrofuran; for example, the volume ratio of ethanol to tetrahydrofuran is (6 to 10):10. Particularly, a small amount of water is further added in step (b), and the volume ratio of water to tetrahydrofuran is (0.2 to 0.5):10. Further, the conditions for the reduction reaction are: reflux reaction for 15 hours to 24 hours.

[0287] When the catalyst is platinum oxide, the conditions for the reduction reaction are: in a hydrogen atmosphere (for example, at 0.5 - 0.8 MPa), reacting at 35°C to 80°C for 20 hours to 70 hours. For example, the conditions for the reduction reaction are: in a hydrogen atmosphere, reacting at 35°C to 50°C for 40 hours to 50 hours.

[0288] Further, after the reaction in step (b) is completed, the compound of formula 5 is purified, and the purification operation can be carried out by a conventional method in the art.

[0289] In some embodiments, the synthesis steps and reaction conditions of the compound of formula 5m are as described in the synthesis method of the compound of formula 5 above, except that the compound of formula 4 is replaced by the compound of formula 4m.

[0290] In some embodiments, the synthesis method of the compound of formula 6 is step (c): in an organic solvent, cyclizing the compound of formula 5 under the action of an acid to obtain the compound of formula 6

[0291] In some embodiments, in step (c), the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, and hydrochloric acid. The organic solvent is selected from at least one of dichloromethane, methanol, ethanol, and isopropanol.

[0292] Particularly, the acid is selected from trifluoroacetic acid, and the organic solvent is isopropanol.

[0293] In some embodiments, in step (c), the molar ratio of the compound of formula 5 to the acid is 1:(1.5 to 2).

[0294] In some embodiments, step (c) is specifically: the compound of formula 5 in isopropanol, refluxing and reacting for 1 hour to 3 hours under the action of trifluoroacetic acid; for example, the reaction time is 1.5 hours to 3 hours.

[0295] Further, after the reaction in step (c) is completed, the compound of formula 6 is purified, that is, the reaction solution is suction filtered, the filter cake is rinsed with isopropanol, and dried to obtain the purified compound of formula 6.

[0296] In some embodiments, the synthesis steps and reaction conditions of the compound of formula 6m are as described in the synthesis method of the compound of formula 6 above, except that the compound of formula 5 is replaced by the compound of formula 5m.

[0297] In some embodiments, the synthesis method of the compound of formula 7 is step (d): in an organic solvent, the amino protecting group of the compound of formula 6 is removed to obtain the anti-tumor compound of formula 7.

[0298] In some embodiments, in step (d), the organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, and isopropanol. In particular, the organic solvent is toluene.

[0299] In some embodiments, in step (d), a catalyst can also be added, and the catalyst is selected from at least one of formic acid, acetic acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid. In particular, the catalyst is selected from trifluoroacetic acid.

[0300] Further, an alcohol or a phenol is also added in step (d), the alcohol is selected from methanol and / or ethanol; the phenol is selected from phenol and / or p-methoxyphenol. Further, for example, the addition amount of the alcohol or the phenol is 1 to 2 molar equivalents of the compound of formula 6.

[0301] Further, after the reaction in step (d) is completed, the compound of formula 7 is purified, and the purification operation can be carried out by a conventional method in the art.

[0302] In some embodiments, the synthesis steps and reaction conditions for synthesizing the compound of formula 7 by replacing the compound of formula 6 with the compound of formula 6m are as described in the synthesis method of the compound of formula 7 above.

[0303] In some embodiments, the compound of formula 7 can also be directly synthesized in one step from the compound of formula 5M. The reaction conditions are: in an organic solvent, the compound of formula 5M reacts under the action of an acid to obtain the compound of formula 7. For example, under the action of trifluoroacetic acid, reflux for 20 - 40 hours. The organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, and isopropanol.

[0304] In some embodiments, the synthesis method of the anti-tumor compound of formula 7 further includes the step of synthesizing the compound of formula 2M:

[0305] (i) In a solvent, the compound of formula 2-1 is subjected to a nitration reaction with nitric acid to obtain the compound of formula 2-2;

[0306] (ii) In an organic solvent, the compound of formula 2-2 undergoes an amino protection reaction with an amino protecting reagent to obtain the compound M of formula (2-3);

[0307] (iii) In an organic solvent, the phthaloyl group is removed from the compound M of formula (2-3) to obtain the compound 2M of formula 2;

[0308] The reaction formula is as follows:

[0309]

[0310] Wherein, the amino protecting reagent is Boc2O, CbzCl, TosCl, FmocCl, PMBBr, MOMCl, EOMCl, tert-butanol, isobutene, BnCl, acetic anhydride, SEMCl, TrtCl or DHP, such as Boc2O, CbzCl, TosCl, FmocCl, PMBBr, TrtCl or DHP; P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, such as Boc, Cbz, Tos, Fmoc, PMB, Trt or THP; P1 is connected to any N atom on the ring where it is located, preferably P1 is connected to the N atom adjacent to the methyl group on the ring where it is located. Preferably, the amino protecting reagent is TrtCl or DHP; P1 is selected from Trt or THP.

[0311] In some embodiments, the compound M of formula (2-3) includes the following compound of formula 2-3 and the compound of formula (2-3)m:

[0312]

[0313] In some embodiments, the solvents in step (i) are such as concentrated sulfuric acid, acetic anhydride, acetic acid;

[0314] In some embodiments, the conditions for the nitration reaction in step (i) are: reacting in concentrated sulfuric acid at 10°C to 20°C for 0.5 hour to 2 hours.

[0315] Furthermore, the mass-volume ratio of the compound of formula 2-1 to concentrated sulfuric acid is 100 g : (150 to 250) ml.

[0316] Furthermore, after the nitration reaction is completed, the obtained compound of formula 2-2 is easy to filter and has good solubility in solvents such as tetrahydrofuran, dichloromethane, acetonitrile, etc., making the selection of the reaction solvent more diverse.

[0317] In some embodiments, different reaction conditions are set in step (ii) according to the nature of the amino protecting reagent. In particular, when the amino protecting reagent is TrtCl, the reaction conditions for step (ii) are: under the action of a base, reacting at 60 °C to 100 °C for 1 hour to 48 hours; when the amino protecting reagent is DHP, the reaction conditions for step (ii) are: under the action of p-toluenesulfonic acid or pyridinium p-toluenesulfonate, refluxing at 60 °C to 100 °C for 3 hours to 48 hours.

[0318] In some embodiments, the organic solvent for the reaction in step (ii) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and acetonitrile.

[0319] In particular, when the amino protecting reagent is TrtCl, the reaction conditions for step (ii) are: under the catalysis of triethylamine, reacting in acetonitrile under reflux for 1 hour to 3 hours.

[0320] In some embodiments, the reaction conditions for removing the phthaloyl group in step (iii) are: under the action of hydrazine hydrate, refluxing in an organic solvent for 1 hour to 3 hours, and the organic solvent is selected from one or more of ethanol, tetrahydrofuran, and acetonitrile.

[0321] In some embodiments, the method for synthesizing the antitumor compound of formula 7 further includes the synthesis step of the compound of formula 1:

[0322] In an organic solvent, the compound of formula 1-1 and the compound of formula 1-2 are subjected to a coupling reaction to obtain the compound of formula 1;

[0323] The reaction formula is as follows:

[0324]

[0325] Wherein, X1, X2, and X3 are each independently selected from a halogen. Preferably, X1, X2, and X3 are each independently selected from chlorine.

[0326] Furthermore, the conditions for the coupling reaction between the compound of formula 1-1 and the compound of formula 1-2 are: under the action of iron(III) acetylacetonate, reacting at -70 to -60 °C.

[0327] The present invention also provides an intermediate for preparing the antitumor compound of formula 7, having the following structural formula:

[0328]

[0329] Preferably, the intermediate has the following structure:

[0330]

[0331] Wherein, X1 and X2 are each independently selected from a halogen;

[0332] P1 is selected from Trt or THPP1 is connected to any N atom on the ring where it is located. Preferably, P1 is connected to the N atom adjacent to the methyl group on the ring where it is located.

[0333] The present invention also provides an intermediate for preparing the antitumor compound of formula 7, which is characterized by having the following structural formula:

[0334]

[0335] Preferably, it has the following structure:

[0336]

[0337] Wherein, P1 is selected from Trt or THP;

[0338] The compound of formula 6M is a complex containing 1 molecule of trifluoroacetic acid and 1 molecule of isopropanol.

[0339] The following further elaborates the present invention through examples. However, the protection scope of the present invention is not limited by these examples.

[0340] The raw materials used in the examples of the present invention are all commercially available products with a purity of chemically pure.

[0341] Example 1

[0342] Synthesis of the compound of formula 1'

[0343]

[0344] Prepare a THF solution of (2-chlorophenyl)magnesium chloride: Dissolve (2-chlorophenyl)magnesium chloride (27.34 mol) in THF solution (50.44 L, 0.542 M), and keep it insulated under anaerobic conditions at -5 to 5 °C for standby.

[0345] Prepare a THF solution of 4,6-dichloronicotinoyl chloride: Add 4,6-dichloronicotinoyl chloride (3.85 kg, 18.32 mol) to THF (25.0 L) and ferric acetylacetonate (193.16 g, 0.55 mol, 0.03 eq) to form a solution (28.0 L, 0.651 M) for standby.

[0346] Prepare dilute hydrochloric acid: Add 2.8 L of concentrated hydrochloric acid and 5.6 L of water to a 100 L reaction kettle, and control the temperature at 5 to 15 °C for preparation for quenching.

[0347] Set the reaction temperature of the microreactor to -70 to -60 °C. Add the THF solution of (2-chlorophenyl)magnesium chloride and the THF solution of 4,6-dichloronicotinoyl chloride into the microreactor. After reaction, obtain the reaction solution of (2-chlorophenyl)(4,6-dichloropyridin-3-yl)methanone. Introduce the reaction solution into the prepared dilute hydrochloric acid for quenching. Separate the layers to obtain a yellow and clear organic phase, and concentrate it. Add MTBE (17.5 L) to the concentrated residue, separate the layers; after concentrating the obtained organic phase to remove the solvent, add 2 L of n-heptane to obtain a brownish-yellow crude product. Add 3.3 L of ethanol and 9.9 L of n-heptane to the crude product, heat to 60 °C until it dissolves clearly, then cool to 5 to 10 °C, filter, and dry the filter cake to obtain 2.78 kg of pale yellow powder, with a yield of 53.3%.

[0348] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 8.61 - 8.57 (m, 1H), 8.02 (s, 1H), 7.70 - 7.62 (m, 3H), 7.55 - 7.51 (m, 1H).

[0349] Synthesis of Compound of Formula 1″

[0350] Step 1: Synthesis of (6-bromopyridin-3-yl)(2-chlorophenyl)methanol

[0351]

[0352] Add anhydrous tetrahydrofuran (500 mL) and 2,5-dibromopyridine (100.0 g, 0.42 mol, 1.0 eq) into a 2 L four-necked flask. Stir and cool the mixture to 2 °C in an ice-water bath. Dropwise add isopropylmagnesium chloride (210.5 mL, 2.0 M, 0.42 mol, 1.0 eq), controlling the temperature not to exceed 10 °C, and finish dropping in about 0.5 h. Stir at room temperature (20 °C) for 1 h, then cool to 10 °C in an ice-water bath, and dropwise add the THF (200 mL) solution of 2-chlorobenzaldehyde (62.3 g, 0.443 mol, 1.05 eq), finishing dropping in about 0.5 h. Stir at 10 °C for 2 h. TLC shows that the reaction is completed. Add saturated ammonium chloride aqueous solution (300 mL) to the reaction system, stir for 10 minutes, then separate the layers. Concentrate the organic phase to obtain a yellow oil. Extract the aqueous phase with ethyl acetate (1.0 L × 2), combine it with the previously obtained yellow oil, wash with water (500 mL), wash with saturated brine (500 mL), dry over anhydrous Na2SO4, and concentrate to obtain a brown oil (140 g of crude product).

[0353] Step 2: Synthesis of (6-bromopyridin-3-yl)(2-chlorophenyl)methanone

[0354]

[0355] (6-Bromopyridin-3-yl)(2-chlorophenyl)methanol (140 g crude) was dissolved in DCM (1.3 L), and TEMPO (1.51 g, 9.4 mmol) and NaBr (1.92 g, 18.8 mmol) were added. The temperature was lowered to 3 °C in an ice-water bath, and an aqueous NaClO solution (1.34 mol / L, 600 L, 0.71 mol) neutralized with NaHCO₃ (45.0 g) was added dropwise. The temperature during the addition did not exceed 20 °C. After the addition was complete, the mixture was stirred for 10 minutes, and TLC showed that the reaction was complete. The layers were separated, the aqueous phase was extracted with DCM (1.0 L), the organic phases were combined, washed with water (1.0 L), washed with saturated brine (1.0 L), dried over anhydrous Na₂SO₄, concentrated to obtain a yellow oil, and the crude product was slurried with (150 mL methyl tert-butyl ether / 500 mL petroleum ether) to obtain a yellow solid (50.3 g, yield: 39.7% over two steps).

[0356] Step 3: Synthesis of (6-bromo-4-iodopyridin-3-yl)(2-chlorophenyl)methanone

[0357]

[0358] Under nitrogen protection, lithium tetramethylpiperidide / magnesium chloride solution (281 mL, 1.5 mol / L, 0.43 mol, 2.5 eq) was added to a 2 L four-necked flask, and the temperature was lowered to -65 °C in a dry ice / ethanol bath. A solution of (6-bromopyridin-3-yl)(2-chlorophenyl)methanone (50.0 g, 0.17 mol, 1.0 eq) in tetrahydrofuran (50 mL) was added dropwise over about 0.5 h. Then the temperature was raised to -45 °C and stirred for 1 h, and then lowered to -65 °C again. A solution of I₂ (129.3 g, 0.51 mol, 3.0 eq) in tetrahydrofuran (400 mL) was added dropwise over about 1 h. After stirring for 20 minutes, TLC showed that the reaction was complete. Saturated aqueous ammonium chloride solution (500 mL) and saturated aqueous NaHSO₃ solution (500 mL) were added to the reaction system, stirred for 15 minutes, filtered, the insoluble matter was washed with ethyl acetate (500 mL × 2), the filtrates were combined, the layers were separated, the aqueous phase was extracted with ethyl acetate (1.0 L × 2), all the organic phases were combined, washed with water (800 mL), washed with saturated brine (800 mL), dried over anhydrous Na₂SO₄, concentrated to obtain a yellow solid, slurried with methyl tert-butyl ether (500 mL) / petroleum ether (500 mL), and dried to obtain a yellow solid (30 g, yield: 41.8%).

[0359] Example 2

[0360] Synthesis of Compound 2′

[0361] Step 1: Synthesis of Compound 2-2

[0362]

[0363] Add concentrated sulfuric acid (7.5 L) to a four-necked reaction flask and stir evenly. Cool the temperature of the system to below 20 °C in an ice-water bath. Add the compound of Formula 2-1 (3590 g, 15.80 mol, 1.0 eq) in batches, and control the temperature of the system at 10 to 20 °C. Slowly add concentrated nitric acid with a mass fraction of 63% (1896.4 g, 18.96 mol, 1.2 eq) to the reaction system. After the addition is complete, remove the ice-water bath and react at 10 to 20 °C for 1 hour. TLC (DCM:MeOH = 20:1) was used to detect the complete conversion of the raw materials. Slowly pour the reaction solution into 36 kg of ice water, filter by suction. After suction drying, add the filter cake to a 50 L wide-mouth bucket, add 36 L of water, stir for half an hour, filter by suction, and rinse the filter cake with water (6 L). The filter cake was dried to a constant weight (about 72 hours) to obtain the compound of Formula 2-2, off-white solid (4160 g, yield: 96.7%, HPLC purity 95.5%).

[0364] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 14.23 (br, 1H), 8.08 - 7.97 (m, 4H), 2.64 (s, 3H).

[0365] Step 2: Synthesis of the compound of Formula 2-3'

[0366]

[0367] Add ACN (38 L) to a reaction kettle, add the compound of Formula 2-2 (4140 g, 15.21 mol, 1.0 eq) and TEA (1847 g, 18.25 mol, 1.2 eq) with stirring, stir evenly, and add triphenylmethyl chloride (4664 g, 16.73 mol, 1.1 eq). Heat the system to reflux (82 °C) for 2 hours until the reaction is complete. Cool to 25 °C, filter by suction, and wash the filter cake with ACN twice (4 L * 2 times). After suction drying, slurry the filter cake with 30 L of water for 2 hours, filter by suction, wash the filter cake with water twice (4 L * 2 times), and dry the filter cake in a forced-air drying oven at 50 °C for 24 hours to obtain the compound of Formula 2-3', white solid (6920 g, HPLC: 99.7%, yield: 88.4%).

[0368] 1 HNMR (400 MHz, CDCl3) δ (ppm): 7.97 - 7.92 (m, 2H), 7.82 - 7.78 (m, 2H), 7.41 - 7.33 (m, 9H), 7.22 - 7.19 (m, 6H), 2.08 (s, 3H).

[0369] Step 3: Synthesis of the compound of Formula 2'

[0370]

[0371] Divide THF (55 L) evenly into four 20-L four-necked flasks. While stirring, add the compound of formula 2-3' (6900 g, 13.41 mol, 1.0 eq) and N2H4·H2O with a mass fraction of 85% (1580 g, 26.82 mol, 2.0 eq) respectively. Heat up to reflux, and the reaction is complete in 3 hours. Let it cool naturally, then filter by suction. The filter cake is rinsed twice with THF (2 L * 2 times). The filtrate is concentrated under reduced pressure in a 50°C water bath to remove 24 L of THF. The remaining filtrate is transferred to a 50-L reaction kettle, heated up to reflux, and 95% ethanol (36 L) is slowly added. A yellowish-green solid slowly precipitates, and stir for 2 hours. Cool to room temperature and stir for crystallization overnight. Filter by suction. The filter cake is rinsed once with 2 L of 95% ethanol, and the filter cake is dried to obtain the compound of formula 2′, a yellowish-green powdery solid (4480 g, HPLC: 100.0%, yield: 86.9%).

[0372] 1 HNMR (400 MHz, CDCl3) δ (ppm): 7.38 - 7.36 (m, 9H), 7.25 - 7.22 (m, 6H), 5.43 (s, 2H), 2.46 (s, 3H).

[0373] Synthesis of Compound 2″

[0374] Step 1: Synthesis of 2-(5-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)isoindoline-1,3-dione

[0375]

[0376] Add anhydrous acetonitrile (270 mol), p-toluenesulfonic acid (1.72 g, 0.01 mol, 0.1 eq), and pyridine (0.79 g, 0.01 mol, 0.1 eq) to the reaction flask. Heat up to 50°C and stir for 2 hours. Add the compound of formula 2-2 (27.2 g, 0.1 mol, 1.0 eq), heat up to reflux, and after 1 hour, add DHP (16.8 g, 0.2 mol, 2.0 eq) dropwise. After refluxing for about 20 hours, concentrate the reaction solution. The residue is slurried with ethyl acetate (90 mL) for 1 hour, filtered, and the filter cake is dried to obtain 28.6 g of the compound of formula 2-3″, with a yield of 80.3%.

[0377] 1HNMR(400MHz, DMSO-d6) δ(ppm): 8.08 - 7.98 (m, 4H), 5.76 - 5.71 (m, 1H), 4.01 - 3.75 (m, 2H), 2.76 (s, 3H), 2.30 - 2.16 (m, 1H), 1.98 - 1.94 (m, 2H), 1.72 - 1.67 (m, 1H), 1.57 - 1.56 (m, 2H).

[0378] Step 2: Synthesis of 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine

[0379]

[0380] Add compound of formula 2-3" (569.4 g, 1.6 mol, 1.0 eq) and THF (5.7 L) to a reaction flask, heat to reflux, and dropwise add hydrazine hydrate (85%) (141.1 g, 2.4 mol, 1.5 eq) over about half an hour. Continue refluxing for about 8 hours. When the reaction is complete by TLC (PE:EA = 2:1), cool to 20 - 25 °C, filter by suction, and concentrate the filtrate to obtain 303 g of crude product. Add 3 L of 95% ethanol to the crude product, heat to reflux, cool to room temperature, and filter to obtain the compound of formula 2″, a yellowish-green solid. Yield = 62.5%.

[0381] 1 HNMR(400MHz, DMSO-d6) δ(ppm): 6.15 (s, 2H), 5.42 - 5.38 (m, 1H), 3.91 - 3.87 (m, 1H), 3.69 - 3.65 (m, 1H), 2.58 (s, 3H), 2.17 - 1.98 (m, 1H), 1.98 - 1.93 (m, 1H), 1.81 - 1.76 (m, 1H), 1.66 - 1.52 (m, 3H).

[0382] Example 3

[0383] Synthesis of compound of formula 4′ [(2-chlorophenyl)(4-((5-methyl-4-nitro-1-trityl-1H-pyrazol-3-yl)amino)-6-morpholinopyridin-3-yl)methanone]

[0384] Step 1: Synthesis of (6-chloro-4-((5-methyl-4-nitro-1-trityl-1H-pyrazol-3-yl)amino)pyridin-3-yl)(2-chlorophenyl)methanone

[0385]

[0386] Add NaHH (10.0 g) to 2-MeTHF (600 mL). After the temperature rises to 50 °C, add compound 2' (38.4 g, 0.1 mol). After stirring for 1 hour, add compound of formula 1' (28.5 g, 0.1 mol). React for 6 - 8 hours until the reaction is complete. After cooling to 20 - 25 °C, add acetic acid (9 g) dropwise. Add 200 ml of water and stir to separate layers. After concentrating the organic phase to about 100 ml, add ethanol (300 mL). After refluxing for 4 - 6 hours, turn off the heating. After cooling to 20 - 25 °C, filter and dry to obtain compound of formula I', 41.4 g of yellow solid, yield = 65.4%, which is directly used for the next step.

[0387] Step 2: Synthesis of (2-chlorophenyl)(4-((5-methyl-4-nitro-1-trityl-1H-pyrazol-3-yl)amino)-6-morpholinopyridin-3-yl)methanone

[0388]

[0389] Add compound of formula I' (41.4 g), morpholine (17.1 g), and 2-MeTHF (400 mL) to a reaction flask. Heat to 80 °C and react for 12 - 16 hours. After concentrating the reaction solution to about 200 ml, add ethanol (300 mL) under reflux. After refluxing for 1 hour, cool to 20 - 25 °C, filter, and dry to obtain compound of formula 4', 41 g of yellow solid, yield = 91.7%.

[0390] Example 4

[0391] Step 1: Synthesis of compound of formula 4″ (2-chlorophenyl)(4-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-6-morpholinopyridin-3-yl)methanone

[0392]

[0393] Place sodium hydride (87.36 g, 2.18 mol) with a mass fraction of 60% into a 10 L three-necked flask, add 2-MeTHF (4.3 L), and the system becomes milky and turbid. Stir the system at 45 - 50 °C for 1 hour. Add the compound of formula 2″ (197.4 g, 0.87 mol) in portions. The system changes from yellow to brown. After stirring for 1 hour, add the compound of formula 1′ (231.5 g, 0.81 mol) and react at 45 - 50 °C for 2.5 hours. Monitor by HPLC. After the reaction is completed, cool the temperature to 12 °C, add acetic acid (78.61 g, 1.31 mol) in portions. The internal temperature rises to 18 °C, then add morpholine (228.3 g, 2.62 mol) and react at 90 °C for 15 hours. Monitor the reaction by HPLC until it is completed. Cool the temperature to 20 - 25 °C, add 2 L of water, separate the layers, concentrate the organic phase, add 1 L of ethyl acetate and slurry for 2 - 4 hours, filter, and dry the filter cake by blowing air to obtain the compound of formula 4″, 218 g of yellow solid, with a yield of 51.2%.

[0394] Step 2: Synthesis of the compound of formula 7, 4-(5-(2-chlorophenyl)-3-methyl-2,10-dihydropyrazolo[4,3-b]pyrido[4,3-e][1,4]diazepin-8-yl)morpholine

[0395]

[0396] Dissolve 4″ (1 g, 1.90 mmol) in 60 ml of acetic acid, add 6 ml of water and 300 mg of Pd / C, and react under hydrogen for 24 hours. Filter, concentrate the mother liquor, add 50 ml of water, and a large amount of yellow solid precipitates. Filter and dry to obtain 720 mg of the compound of formula 6″, with a yield of 80%.

[0397] Dissolve 6″ (1 g, 2.09 mmol) in methanol, add p-toluenesulfonic acid (0.43 g, 2.50 mmol), stir at room temperature for 16 hours, raise the temperature to 55 °C, and add additional p-toluenesulfonic acid (0.28 g, 1.6 mmol). React for 3 hours, concentrate, and perform column chromatography to obtain the product 7 as a yellow solid.

[0398] Molecular formula: C 20 H 19 ClN6O Molecular weight: 394.86 LC-MS (Pos, m / z) = 395.22 [M + H] + .

[0399] Example 5

[0400] Synthesis of the compound of formula 7

[0401] Step 1: Synthesis of the compound of formula 4′, (2-chlorophenyl)(4-((5-methyl-4-nitro-1-trityl-1H-pyrazol-3-yl)amino)-6-morpholinopyridin-3-yl)methanone

[0402]

[0403] Add 2-MeTHF (15 L) to the reaction flask, add magnesium sulfate (500 g, 4.15 mol) under stirring, sodium hydride with a mass fraction of 60% (260 g, 6.50 mol), stir at 50 °C for 2 hours, add the compound of formula 2' (1000 g, 2.60 mol) in batches. The system turns brownish-yellow. After stirring for 1 hour, the system turns brown, and then add the compound of formula 1' (820 g, 2.86 mol). React at 46 - 60 °C for 3.5 hours. Monitor by HPLC until the reaction of the compound of formula 1' is completed. Add acetic acid (234 g, 3.90 mol) in batches. The system becomes a brown suspension. Add morpholine (680 g, 7.80 mol), and reflux for 15 hours. Monitor by HPLC until the reaction ends. Cool the system to 15 - 25 °C. Add 7.5 L of water, separate the layers. Dry the organic phase with anhydrous magnesium sulfate, filter, concentrate the filtrate to about 1 - 2 L of solvent remaining, add 5 L of toluene and 15 L of ethanol, slurry at 78 °C for 2 hours, cool to room temperature, filter, and dry to obtain 1250 g of a yellow solid with a yield of 70.3%.

[0404] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 12.55 (s, 1H), 7.89 (s, 1H), 7.60 - 7.52 (m, 2H), 7.50 - 7.49 (m, 2H), 7.42 - 7.33 (m, 9H), 7.29 - 7.27 (m, 6H), 7.21 (s, 1H), 3.60 - 3.50 (m, 4H), 3.70 (s, 4H), 2.07 (s, 3H).

[0405] Step 2: Synthesis of the compound of formula 5' (4-((4-amino-5-methyl-1-trityl-1H-pyrazol-3-yl)amino)-6-morpholinopyridin-3-yl)(2-chlorophenyl)methanone

[0406]

[0407] (Example 1) Add water (300 mL), ethanol (95%, 7.5 L), ammonium chloride (30.30 g, 0.57 mol), and iron powder (950 g, 17 mol) to a 20 L reaction flask. Stir at 55 - 60 °C for 1.5 h, add THF (7.5 L) and the compound of formula 4′ (775 g, 1.13 mol). Reflux for 5 h, add additional iron powder (320 g, 5.66 mol), and reflux for 15 h. Monitor the reaction by HPLC until completion. Filter the reaction mixture through diatomaceous earth (1.5 kg) while it is hot. Wash the filter cake with THF (3 L). Concentrate the filtrate to approximately 5 L of solvent remaining, add 5 L of ethanol, and slurry at 65 °C for 3 h. Cool to room temperature, filter, wash the filter cake with 4 L of ethanol, and dry to obtain 590 g of a yellow solid with a yield of 79.6%.

[0408] 1 HNMR(300MHz,CDCl3)δ(ppm): 11.42(s, 1H), 8.04(s, 1H), 7.47 - 7.23(m, 19H), 7.11(s, 1H), 3.67 - 3.63(m, 4H), 3.27 - 3.24(m, 4H), 1.59(s, 3H).

[0409] (Example 2) Add the compound of formula 4′ (6.8 g, 10.0 mmol) and THF (150 mL) to an autoclave. Add platinum oxide (700 mg), introduce hydrogen gas at 0.5 - 0.8 MPa, and react at 40 °C for 46 h. Monitor the reaction by HPLC until completion. Filter the reaction mixture, concentrate the filtrate to approximately 50 mL remaining, add 100 mL of n - heptane dropwise under reflux, cool to room temperature, filter, and dry to obtain 5.5 g of a yellow solid with a yield of 84.6%.

[0410] Step 3: Synthesis of 4 - (5 - (2 - chlorophenyl) - 3 - methyl - 2 - triphenylmethyl - 2,10 - dihydropyrazolo[4,3 - b]pyrido[4,3 - e][1,4]diazepin - 8 - yl)morpholine isopropanolate trifluoroacetate of the compound of formula 6′

[0411]

[0412] Add 20 L of isopropanol to a 50 L reaction kettle, add the compound of formula 5′ (1980 g, 3.03 mol) and TFA (690 g, 6.05 mol). Heat to reflux, after reacting for 2 h, monitor the reaction by HPLC until completion. Cool to 20 °C, filter with suction. Wash the filter cake with isopropanol until the filtrate is clear, and dry to obtain 2300 g of a yellow solid with a yield of 93.8%.

[0413] 1HNMR(400MHz, DMSO-d6) δ (ppm): 9.24 (s, 1H), 7.51 - 7.48 (m, 1H), 7.43 - 7.35 (m, 9H), 7.32 - 7.29 (m, 3H), 7.17 - 7.15 (m, 6H), 6.79 (s, 1H), 6.17 (s, 1H), 3.81 - 3.74 (m, 1H), 3.66 - 3.64 (m, 4H), 3.36 - 3.33 (m, 4H), 1.36 (s, 3H), 1.48 - 1.32 (d, 6H, J == 6.12Hz).

[0414] Step 4: Synthesis of Compound 4-(5-(2-chlorophenyl)-3-methyl-2,10-dihydropyrazolo[4,3-b]pyrido[4,3-e][1,4]diazepin-8-yl)morpholine of Formula 7

[0415]

[0416] Compound of Formula 6' (58.0 g, 71.5 mmol) and methanol (4.6 g, 143.7 mmol) were added to toluene (600 mL), trifluoroacetic acid (8.2 g, 71.9 mmol) was added, and the mixture was heated to reflux for 17 hours. Then the temperature was lowered to 50 °C, and the mixture was filtered by suction. The filter cake was slurried with toluene (400 mL) at 50 °C for 1 hour and then filtered by suction again. The product was dried in a forced-air oven at 100 °C to obtain 32 g of a yellow solid. The obtained solid was dissolved in methanol (300 mL) and water (100 mL), and the pH was adjusted to 7 - 8 with diluted ammonia water. A large amount of yellow solid precipitated out. The mixture was stirred at 50 °C for 1 hour and then filtered by suction. The filter cake was dried to obtain 24 g of a yellow solid, with a purity of 99.7% and a yield of 85.4%.

[0417] 1 H-NMR (DMSO-d6, 400 MHz) 11.57 (s, 1H), 8.29 (s, 1H), 7.32 - 7.47 (m, 4H), 6.89 (s, 1H), 5.95 (s, 1H), 3.61 (m, 4H), 3.31 (m, 4H), 1.97 (s, 3H).

[0418] Example 6

[0419] Step 1: Synthesis of Compound 4-(5-(2-chlorophenyl)-3-methyl-2,10-dihydropyrazolo[4,3-b]pyrido[4,3-e][1,4]diazepin-8-yl)morpholine of Formula 7

[0420]

[0421] Dissolve the compound of formula 5′ (1 g, 1.53 mmol) in DCM (10 mL), and add TFA (350 mg, 3.06 mmol). Stir for 2.5 hours, and a yellow solid precipitates in the system. Heat to reflux, and the yellow turbidity in the system gradually turns into orange-yellow clarity. Stir overnight, react for a total of 24 hours, until the system becomes brown-black and clear. Add EA (100 mL) and saturated aqueous sodium bicarbonate solution, separate the layers, concentrate the organic phase, slurry with 20 mL of EA, and filter to obtain the compound of formula 7.

[0422] Example 7

[0423] The procedure of this example is similar to Step 1 of Example 5, replacing 2-MeTHF with toluene to prepare the compound of formula 4′.

[0424] Example 8

[0425] The procedure of this example is similar to Step 1 of Example 5, replacing 2-MeTHF with acetonitrile to prepare the compound of formula 4′.

[0426] Example 9

[0427] The procedure of this example is similar to Step 1 of Example 5, replacing 2-MeTHF with tetrahydrofuran to prepare the compound of formula 4′.

[0428] Example 10

[0429]

[0430] Add the compound of formula I′ (1.3 g, 2 mmol), morpholine (5 mL, 57 mmol), and potassium carbonate (2.0 g, 14.5 mmol) to DCM (10 mL), heat to 40 °C, after reacting for 2 h, detect by HPLC that the reaction is complete, turn off the heating, filter, add EtOH (10 mL) to the filtrate, heat to reflux for 2 hours, then turn off the heating, cool naturally to 20 - 25 °C, filter, and dry the filter cake to obtain 1.2 g.

[0431] Example 11

[0432]

[0433] Add 2-MeTHF (10 L) to the reaction flask, add 60% sodium hydride (300 g, 7.50 mol) under stirring, heat up to 50 °C, add the compound of formula 2' (1153.2 g, 3 mol) in batches. After stirring for 1 hour, add a 2-MeTHF (2 L) solution of the compound of formula 1' (940.3 g, 3.3 mol). React at 50 °C for 6 hours until the reaction of the compound of formula 1' is completed as monitored by TLC. Cool down to 20 °C, slowly add acetic acid (270 g, 4.5 mol) dropwise. After stirring for 10 minutes, add morpholine (784.8 g, 9 mol), and reflux for 15 hours. Monitor the reaction by HPLC until it ends, then turn off the heating and cool the system to 15 - 25 °C. Wash with water (10 L × 2), dry the organic phase with anhydrous Na2SO4, filter by suction, and wash the filter cake with 2-MeTHF (2 L). Add 200 g of activated carbon to the filtrate, reflux for 1 hour, filter while hot, wash the filter cake with 2-MeTHF (1 L). Evaporate 6 L of the solvent at atmospheric pressure from the filtrate, then add EtOH (8 L), reflux for 1 hour, turn off the heating, and let it cool naturally to 20 - 25 °C. Filter, wash the filter cake with EtOH (1 L), transfer the obtained wet product to DCM (15 L), heat up to reflux, add activated carbon (300 g), stir for 0.5 hour, filter while hot, wash the filter cake with DCM (1 L). Evaporate 2 L of the solvent at atmospheric pressure from the filtrate, add EtOH (12 L), reflux and stir for 4 hours, turn off the heating, and let it cool naturally to 20 - 25 °C. Filter by suction and dry to obtain 1234.5 g of a yellow solid with a yield of 60.1%.

[0434] Example 12

[0435] The procedure of this example is similar to Step 2 of Example 5 (Example 2). Replace platinum oxide with Pt / C, and carry out the reaction to prepare the compound of formula 5', with a yield of over 80%.

[0436] Example 13

[0437] The procedure of this example is similar to Step 2 of Example 5 (Example 2). Replace platinum oxide with Pd / C, and carry out the reaction to prepare the compound of formula 5'.

[0438] Example 14

[0439] The procedure of this example is similar to Step 2 of Example 5 (Example 2). Replace platinum oxide with Pd(OH)2 / C, and carry out the reaction to prepare the compound of formula 5'.

[0440] Example 15

[0441] The procedure of this example is similar to Step 2 of Example 5 (Example 2). Replace platinum oxide with Rh / C, and carry out the reaction to prepare the compound of formula 5'.

[0442] Example 16

[0443] The steps of this example are similar to step 2 of Example 5. Replace THF (Example 2) with a mixture of THF and isopropanol, and carry out the reaction to prepare Compound of Formula 5'.

[0444] Example 17

[0445] The steps of this example are similar to step 3 of Example 5. Replace trifluoroacetic acid (TFA) with p-toluenesulfonic acid, and carry out the reaction to prepare Compound of Formula 6'.

[0446] Example 18

[0447] The steps of this example are similar to step 3 of Example 5. Replace trifluoroacetic acid (TFA) with methanesulfonic acid, and carry out the reaction to prepare Compound of Formula 6'.

[0448] Example 19

[0449] The steps of this example are similar to step 4 of Example 5. Replace methanol with ethanol, and carry out the reaction to prepare Compound of Formula 7, with a yield of over 80%.

[0450] Example 20

[0451] Add Compound of Formula 6' (385 g, 0.47 mol), TFA (138 g, 1.21 mol), and EtOH (55.66 g, 1.21 mol) to DCM (4 L), heat to reflux for reaction. After 1.5 hours, turn off the heat and cool to 20 - 25 °C. Add an aqueous solution of NaOH (66 g) in water (2 L), and a solid precipitates. Stir for 1 hour and then filter by suction. The filter cake is dissolved in 12 L of EtOH + 2 L of water, add 15 g of activated carbon, stir for 0.5 hour, then filter by suction. Concentrate the filtrate to 1.5 L, continue to reflux for 1 hour, cool to 20 - 25 °C, then filter by suction and dry to obtain 114 g of a yellow solid, yield = 61.0%.

[0452] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the scope of protection of the present invention.

Claims

1. An intermediate compound of formula 2-2 for preparing an antitumor compound of formula 7, characterized in that, It has the following structural formula:

2. Intermediate M compound of formula (2-3) for preparing antitumor compound of formula 7, characterized in that, It is prepared from the intermediate formula 2-2 compound described in claim 1, and its structural formula is: P1 is selected from Trt.

3. Intermediate compound of formula 2M for preparing antitumor compound of formula 7, characterized in that, It is prepared from the intermediate formula (2-3)M compound described in claim 2, and its structural formula is: P1 is selected from Trt.

4. An intermediate compound of formula 4M for preparing an antitumor compound of formula 7, characterized in that, It is prepared from the intermediate formula 2M compound described in claim 3, and its structural formula is: P1 is selected from Trt.

5. An intermediate compound of formula 5M for preparing an antitumor compound of formula 7, characterized in that, It is prepared from the intermediate formula 4M compound described in claim 4, and its structural formula is: P1 is selected from Trt.

6. An intermediate compound of formula 6M for preparing an antitumor compound of formula 7, characterized in that, It is prepared from the intermediate formula 5M compound described in claim 5, and its structural formula is: P1 is selected from Trt.

7. An intermediate compound of formula 6M for preparing an antitumor compound of formula 7, characterized in that, It is prepared from the intermediate formula 5M compound described in claim 5, and its structural formula is: P1 is selected from Trt; This formula 6M is a complex containing 1 molecule of trifluoroacetic acid and 1 molecule of isopropanol.

8. A method for synthesizing the intermediate formula 2M compound: (ii) In an organic solvent, the formula 2-2 compound reacts with an amino protecting reagent to carry out an amino protection reaction to obtain the formula (2-3)M compound; (iii) In an organic solvent, the phthaloyl group of the formula (2-3)M compound is removed to obtain the formula 2M compound; The reaction formula is as follows: Among them, The amino protecting reagent is TrtCl.

9. The method according to claim 8, wherein The method for synthesizing the intermediate formula 2M compound further includes: (i) In a solvent, the formula 2-1 compound reacts with nitric acid to carry out a nitration reaction to obtain the formula 2-2 compound; The reaction formula is as follows:

10. The method according to claim 8 or 9, characterized in that, The method for synthesizing the intermediate formula 2M compound: (i) In one or more of concentrated sulfuric acid, acetic anhydride and acetic acid, the formula 2-1 compound reacts with nitric acid, the reaction time is 0.5 - 2 hours, and the reaction temperature is 10 - 20 °C to obtain the formula 2-2 compound; (ii) In one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and acetonitrile, the formula 2-2 compound reacts with an amino protecting reagent to carry out an amino protection reaction, the reaction time is 1 - 48 hours, and the reaction temperature is 60 - 100 °C to obtain the formula (2-3)M compound; (iii) In one or more of ethanol, tetrahydrofuran and acetonitrile, the phthaloyl group of the formula (2-3)M compound is removed, the reaction time is 1 - 3 hours, and the reaction temperature is the reflux temperature to obtain the formula 2M compound; the reaction formula is as follows: Among them, the amino protecting reagent is TrtCl.

11. A method for synthesizing an antitumor compound of formula 7, characterized in that, It includes the following steps: (a1) The formula 2M compound is obtained by using the method described in any one of claims 8 - 10; (a) In an organic solvent, the formula 1 compound and the formula 2M compound carry out an aromatic nucleophilic substitution reaction under the action of a base to obtain the formula IM compound. Whether the formula IM compound is separated or not, it continues to carry out an aromatic nucleophilic substitution reaction with the formula 3 compound to obtain the formula 4M compound; (b) In an organic solvent, the formula 4M compound undergoes a reduction reaction under the action of a catalyst to obtain the formula 5M compound; (c) In an organic solvent, the formula 5M compound is cyclized under the action of an acid to obtain the formula 6M compound; (d) In an organic solvent, the amino protecting group of the formula 6M compound is removed to obtain the formula 7 anti-tumor compound; The reaction formula is as follows: Among them, X1 and X2 are each independently selected from chlorine; P1 is an amino protecting group, and P1 is selected from Trt.

12. The method according to claim 11, characterized in that, In step (a), the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran, and toluene; the base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide; Optionally in step (a), the reaction pressure is 0 to 10 MPa (gauge pressure), for example, atmospheric pressure; the reaction time is 1 to 96 hours, for example, 17 hours; the reaction temperature can be the reflux temperature; Specifically, in the aromatic nucleophilic substitution reaction of the compound of formula 1 and the compound of formula 2M under the action of a base, the reaction time is 3 to 18 hours, for example, the reaction time is 3 to 8 hours; the reaction temperature is 40 °C to 70 °C, for example, the reaction temperature is 40 °C to 60 °C; Specifically, in the continued aromatic nucleophilic substitution reaction with the compound of formula 3, the reaction time is 8 hours to 16 hours, for example, 13 hours to 16 hours; the reaction temperature can be the reflux temperature; The ratio is: solvent: compound of formula 1: compound of formula 2M: compound of formula 3: base = 0.5 - 60 L: 0.1 - 11 moles: 1 mole: 0.3 - 30 moles: 0.2 - 25 moles; for example, 5.8 L: 1.1 moles: 1 mole: 3 moles: 2.5 moles; Specifically, magnesium sulfate is added in the aromatic nucleophilic substitution reaction of the compound of formula 1 and the compound of formula 2M under the action of a base, and acetic acid is added in the continued aromatic nucleophilic substitution reaction with the compound of formula 3, The ratio is: solvent: compound of formula 1: compound of formula 2M: compound of formula 3: base: magnesium sulfate: acetic acid = 0.5 - 60 L: 0.1 - 11 moles: 1 mole: 0.3 - 30 moles: 0.2 - 25 moles: 0.2 - 20 moles: 0.1 - 15 moles, for example, 5.8 L: 1.1 moles: 1 mole: 3 moles: 2.5 moles: 1.6 moles: 1.5 moles; In step (a), for the basic condition described, morpholine can be used as the base without additionally adding other bases, or one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide can be additionally added; and / or and / or In step (b), the organic solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetic acid, and acetonitrile; the catalyst is selected from iron powder, platinum oxide, Pt / C, Pd(OH)2 / C, Rh / C, or Pd / C; Optionally in step (b), when the catalyst is iron powder, the reaction time is 1 to 96 hours, for example, 15 to 24 hours; the reaction pressure is 0 to 10 MPa (gauge pressure), for example, atmospheric pressure; the reaction temperature is the reflux temperature; The ratio is: organic solvent: compound of formula 4M: catalyst = 1 - 130 L: 1 mole: 1 to 150 moles, for example, 13 L: 1 mole: 10 - 18 moles, for example, 13 L: 1 mole: 14 - 18 moles, for example, 13 L: 1 mole: 15 moles; In particular, when the catalyst is iron powder: in step (b), ammonium chloride in an amount of 0.05 - 5 molar equivalents, such as 0.5 molar equivalent, is further added; the solvent is a mixed solvent of ethanol and tetrahydrofuran, for example, the volume ratio of ethanol to tetrahydrofuran is (6 to 10):10; In particular, in step (b), when the catalyst is platinum oxide, Pt / C, Pd(OH)₂ / C, Rh / C or Pd / C, the reaction is carried out in a hydrogen atmosphere at 30°C to 80°C for 20 hours to 80 hours; for example, the reaction is carried out in a hydrogen atmosphere at 60°C to 80°C for 20 hours to 72 hours; the reaction pressure is greater than 0 to 10 MPa (gauge pressure), such as 0.5 - 2 MPa; The ratio is solvent: Compound of formula 4M: catalyst = 1 - 50 mL: 1 g: 0.03 to 0.2 g, such as 22 mL: 1 g: 0.1 g; Optionally in step (b), a small amount of water is further added in step (b), for example, the volume ratio of water to tetrahydrofuran is (0.2 to 2):10; and / or In step (c), the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid and hydrochloric acid; the organic solvent is selected from at least one of dichloromethane, methanol, ethanol and isopropanol; Optionally in step (c), the reaction time is 1 - 96 hours, such as 1.5 - 3 hours; the reaction pressure is 0 to 10 MPa (gauge pressure), such as atmospheric pressure; the reaction temperature is the reflux temperature; the ratio is solvent: Compound of formula 5M: acid = 0.5 - 70 L: 1 mole: 0.220 mole, such as 6.6 L: 1 mole: 2 moles and / or Step (c) specifically is: The Compound of formula 5M is refluxed in isopropanol under the action of trifluoroacetic acid for 1 hour to 3 hours; and / or In step (d), the organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol and isopropanol; In step (d), an acid is further added, and the acid is selected from at least one of formic acid, acetic acid, hydrochloric acid, methanesulfonic acid and trifluoroacetic acid; In step (d), an alcohol or phenol other than the solvent is further added; the alcohol is selected from methanol and / or ethanol, and the phenol is selected from phenol and / or p-methoxyphenol; Optionally in step (d), the reaction time is 1 - 96 hours, such as 17 hours; the reaction pressure is 0 to 10 MPa (gauge pressure), such as atmospheric pressure; the reaction temperature is the reflux temperature; the ratio is solvent: Compound of formula 6M: acid: alcohol or phenol = 10 - 800 L: 1 mole: 0.1 to 10 moles: 0.2 to 20 moles, such as 84 L: 1 mole: 1 mole: 2 moles.

13. The method according to claim 10, wherein, The reaction conditions of step (ii) are: reacting at 60°C to 100°C for 1 hour to 48 hours under the action of a base.

14. The method according to claim 11, wherein It further includes the step of synthesizing the Compound of formula 1: In an organic solvent such as THF, the Compound of formula 1-1 and the Compound of formula 1-2 are subjected to a coupling reaction to obtain the Compound of formula 1; The reaction formula is as follows: Wherein, X1, X2 and X3 are each independently selected from chlorine.

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